The present invention relates generally to drug discovery methods and, more specifically to Nuclear Magnetic Resonance (NMR) methods for identifying compounds that interact with macromolecules.
Two general approaches have traditionally been used for drug discovery: structure-based drug design and screening for lead compounds. Structure-based drug design utilizes a three-dimensional structure model of a drug target to predict or simulate interactions with known or hypothetical compounds. Alternatively, in cases where a three-dimensional structure model of a drug target complexed with a ligand is available, therapeutic drugs can be designed to mimic the structural properties of the ligand, thereby identifying lead compounds for further development.
Screening for lead compounds is another approach that has been used with some success to identify lead compounds for therapeutic targets. Screening involves assaying a library of candidate compounds to identify lead compounds that interact with a drug target. The probability of identifying a lead compound can be increased by providing increased numbers and variety of candidate compounds in the library to be screened. Synthetic methods are available for creating libraries of compounds and include, for example, combinatorial chemistry approaches in which selected chemical groups are variously combined to generate a library of candidate compounds having diverse combinations of the selected chemical groups. In addition, advances have been made to increase the through-put for a number of screening methods. However, for many drug targets the throughput of available screens is prohibitively low. Furthermore, even in cases where high throughput detection is available, limitations on available resources for obtaining a library with sufficient size or diversity, or for obtaining a sufficient quantity of the drug target to support a large screen, can be prohibitive.
The efficiency of library screening approaches can be increased by combining structure-based drug design with the methodologies currently available for library screening. In particular, the probability of identifying a lead compound in a screening approach can be increased by using focused libraries containing member compounds having a higher probability of interacting with the drug target. Focused libraries having members with a limited range of structural or functional variations have been obtained based on variations predicted from structure-based drug design methods and used to screen for candidate drugs.
However, for many drug targets of interest, three-dimensional structure models are not presently available. Although methods for structure determination are evolving, it is currently difficult, costly and time consuming to determine the structure of a macromolecule drug target at sufficient resolution to render structure-based drug design practical. It can often be even more difficult to produce a macromolecule-ligand complex in a condition allowing a sufficiently resolved structure model of the complex. The typically long time period required to obtain structure information useful for developing drug candidates is particularly limiting with regard to exploiting the growing number of potential drug targets identified by genomics research.
Thus, there exists a need for methods to reduce the size and diversity of candidate libraries required to screen for lead compounds. The present invention satisfies this need and provides related advantages as well.